A major problem in the chemotherapy of cancer in man is the variation in response of a single histological type of malignancy to a given drug. It is also a well-established fact that individual advanced transplanted tumors of similar size and histology exhibit responses to a drug that range from minimal to complete regression and cure. That tumor-to-tumor variability in perfusion and drug distribution was a major factor in the variable response of mammary adenocarcinoma 16/C to melphalan was demonstrated during the initial period of this grant. The distribution of two nitroimidazole radiation sensitizers was uniform in the same tumors that exhibited limited and uneven distribution of melphalan. We propose to investigate the distribution of other agents or classes of agents such as mitomycin C, an antibiotic with unique pharmacological properties, in tumor regions of low perfusion, as delineated by a visible dye. Prior or simultaneous treatment of tumor-bearing mice with agents to modify the distribution of melphalan will be investigated. We plan to investigate the tumor-to-tumor variability of perfusion and drug distribution in a second histological type of murine tumor, the M5076 sarcoma, and the A549 human lung adenocarcinoma as a xenograft in athymic mice. We plan to seek a correlation between readily measurable clinical chemistry and hematology parameters, the plasma levels of melphalan following a standard dose, and concentrations of melphalan in tumor regions of high and low perfusion. Similar correlations will be attempted in mice pretreated with melphalan and in mice following dose adjustments to reduce toxicity. We further propose to investigate intracellular levels of melphalan in tumor regions of high and low perfusion. These studies have immediate clinical significance for chemotherapy of tumors of the same histologic type and exhibit variable responses to effective chemotherapy and for rational dose adjustment.